The present invention relates to compositions and methods for enhancing the immune response in mammals. Such mammals include human infants, humans with depressed immune response and normal humans who would benefit from an enhanced immune response. The compositions may be applied in vivo or ex vivo.
The immune system of mammals protects the host from microbial and viral invasion and is essential for survival. Individuals born with severe deficits in immunity must be confined to a sterile environment in order to survive. Individuals with acquired immunodeficiency due to infection with the human immunodeficiency virus or chemotherapy, can succumb to opportunistic infections that would not make a healthy human seriously ill. Even healthy humans experience episodes of infection from influenza, respiratory diseases, or such, which are caused by or result in a less than optimal immune function. Human infants, in particular, have immature immune systems and would benefit from compositions and methods effective to enhance their immune systems. The cells comprising the immune system may benefit from ex vivo enhancement of the immune response.
The immune system is complex. Following presentation of an antigen, as from a pathogenic microorganism or virus, cells of the lymphoid and myelogenous tissues undergo rapid clonal expansion. Including in these reacting cells are antigen-presenting macrophages which facilitate the introduction of antigen to B- and T-cells. T-cells include natural killer cells and T-helper cells, which enhance the ability of B-cells to make antigen-specific antibodies. All of these cells interact to suppress and eliminate the infection.
Lymphoid and myelogenous tissues at rest have a high rate of cell proliferation with a rapid protein turnover. When activated, these tissues have an even higher metabolic rate, the xe2x80x9crespiratory burst.xe2x80x9d Oxygen and nutrient consumption increase many-fold as the cells proliferate, differentiate and produce antibodies and degradative proteins with which to combat the invading pathogen. It is well known that individuals with nutritional deficiencies are unable to mount an effective immune response. Among the deficiencies identified as contributing to a poor immune response are the lack of vitamins A, B1, B2, B6, B12, C, E and folic acid. Low protein and insufficient caloric intake also depress the immune response. Newborn infants have suboptimal immune responses and are susceptible to infection. When growth retardation, nutritional deficiency and low birth weight complicate the picture, impairment of immunocompetence is more marked. Elderly persons often have reduced immunocompetence due to the common occurrence of increased nutritional deficiencies at a time of life when better nutritional intake is necessary to compensate for decreased metabolic efficiency.
Among the conditions that are characterized by an impaired immune response are malignancies, chronic fatigue syndrome, cardiac cachexia, acute and chronic stress such as extreme physical activity or anxiety, depression, fungal infections, acute, subacute and chronic infection, diabetes, xe2x80x9cjet lagxe2x80x9d syndrome, eating disorders, and trauma including surgery, and the like. It is unknown whether the impairment of the immune system is the primary or contributory cause of these conditions, but it is well known that individuals suffering from these conditions are unable to mount a vigorous immune response and are especially susceptible to debilitating or even life-threatening infections ranging from the common cold to septic shock. Not wishing to be bound by theory, it is proposed that a method of enhancing the immune response, while not curing these conditions, would ameliorate some of the symptoms.
Because the proliferating and protein-synthesizing leukocytes have increased requirements for DNA and RNA, several researchers have administered nucleotides and/or nucleosides to provide pre-formed DNA and RNA. Typical of these studies is that of Carver et al. (Journal of Parenteral and Enteral Nutrition (1990) 14:18) where weanling mice fed up to 0.035% w/w nucleotides (Sigma Chemical, St. Louis, Mo.) show increased NK activity, macrophage activation and spleen weight. Other workers found that mice subjected to the chemotherapeutic agent cyclophosphamide or low protein diets, either of which depresses the immune system profoundly, were benefited from administration of a mixed nucleotide/nucleoside composition. (Adje et al. (1995) American Journal of Nutrition; Matsumoto et al. (1995) Nutrition 11:296.)
Several workers have found that adding the monosaccharide D-Ribose has a salutary effect on the enhancement of energy or the prevention of exercise-induced pain and cramping. See, for example, U.S. Pat. Nos. 6,159,942 and 6,159,943. The tissues involved in these studies were skeletal muscles. Nothing was known of the effect of D-Ribose on the immune response. It has been thought by those skilled in the art that D-Ribose was cytotoxic to a number of cells, including immune cells. Marini et al (Proceedings of the Society for Experimental Biology and Medicine (1985) 180:246-257) tested the effects of D-Ribose and deoxy-D-Ribose at levels from 12.5 to 50 mM on the incorporation of tritiated thymidine in various cell cultures and concluded: xe2x80x9cthey deeply derange metabolic processes in both dividing and nondividing cells.xe2x80x9d
A need remains for compositions and methods to enhance the immune response.
The present invention provides the administration of an effective dose of D-ribose to enhance the immune response in a mammal by inducing proliferation, differentiation and maturation of leukocytes. The D-Ribose may be administered orally or parenterally. A preferred effective dose is 0.2 to 20 gm of D-Ribose. A more preferred effective dose is 0.5 to 10 gm of D-Ribose. A most preferred effective dose is 0.5 to 5 gm of D-Ribose. The doses may be administered once, twice or three times per day. The leukocytes to be enhanced in vivo may be endogenous or obtained via an autogenous transfusion or a transfusion from a donor or donors. The D-Ribose may also be administered ex vivo to isolated immune cells, which are cultured in the presence of D-Ribose until proliferation and differentiation are achieved and then transfused into a recipient. The preferred concentration of D-Ribose in the culture medium is 2 to 20 mM, more preferably 5 to 15 mM and most preferably 10 mM.